The primary objective of this study is to examine the hypothesis that muscarinic activity as displayed by muscarine is a result of binding of the three heteroatoms at a receptor(s). The specific groups to be varied are the ether oxygen and the hydroxyl group. Synthesis of the desether analog and its isomers are detailed in this proposal. Biological evaluation will be directed toward establishing with certainty the muscarini potency of each of these compounds. This will require initial screening with the classic guinea pig ileum and chick m. biventor cervicis preparations to establish the muscarinic vs. nicotinic activities. Additional experimental preparations will be carried out as determined by our initial results. Conformational structural investigations will be pursued by x-ray crystallographic studies and by calculations of preferred conformations, both available from on-going programs in our Department. Based on the results of all of these studies we hope to contribute a more definitive picture of the cholinergic receptor requirements. BIBLIOGRAPHIC REFERENCES: R. S. Givens and D. R. Rademacher; Further Studies on Carbocyclic Analogs of Muscarine. Oxidation of Desethermuscarine to Desethermuscarone, J. Med. Chem., 17, 457 (1974). R. S. Givens, D.R. Rademacher, J. K. Kongs and J. Dickerson, Synthetic Entry into Cyclopentyl Analogs of muscarine, Tetrahedron Letts., 3211(1974).